tbuckley/cabot-search huggingface dataset:
Abstract 1628: A small-molecule inhibitor of WRN selectively kills MSI-H cancer cells and phenocopies WRN genetic defects
Authors: Yanhua Rao, Anjana Srivatsan, Marya Liimatta, Diana Munoz, Jeanne Quirit, Jianxia Shi, An Nguyen, Xin Linghu, Federowicz Federowicz, Brian Jones, Melissa Fleury, Zach Newby, Michael P. Dillon, Paul A. Barsanti, Mark R. Lackner, Michael A. White, Yang Lee, Phil Landis, Yang Peng, Michelle Cicchini, Josh Cottom, Leng Nickels, Ed Brnardic, Michael DeMartino, Josh Taygerly
Journal: Cancer Research (2023)

Abstract Werner syndrome protein (WRN) is a RecQ-family helicase involved in the maintenance of genome integrity. Germline mutations in WRN cause premature aging and cancer predisposition. Analysis of systematic RNAi and CRISPR screening data has previously revealed that WRN is essential for the survival of cancer cell lines with high microsatellite instability (MSI-H). We have developed potent and selective small-molecule inhibitors of WRN helicase (WRNi) and showed that pharmacological inhibition of WRN causes lethality and induction of DNA damage markers selectively in MSI-H cancer cell lines compared to microsatellite-stable (MSS) cell lines. Screening of WRNi across a large panel of pooled, barcoded cell lines in the PRISM format revealed selective sensitivity in MSI-H cell lines and showed that pharmacological inhibition of WRN is highly correlated with genetic ablation of WRN across this panel, confirming selectivity for WRN. In vivo evaluation demonstrated robust and MSI-selective tumor regressions. These data provide pharmacological proof-of-concept for the WRN/MSI-H synthetic lethal relationship and support WRN inhibition as a novel therapeutic approach for the treatment of MSI-H cancers. Citation Format: Yanhua Rao, Anjana Srivatsan, Marya Liimatta, Diana Munoz, Jeanne Quirit, Jianxia Shi, An Nguyen, Xin Linghu, Federowicz Federowicz, Brian Jones, Melissa Fleury, Zach Newby, Michael P. Dillon, Paul A. Barsanti, Mark R. Lackner, Michael A. White, Yang Lee, Phil Landis, Yang Peng, Michelle Cicchini, Josh Cottom, Leng Nickels, Ed Brnardic, Michael DeMartino, Josh Taygerly. A small-molecule inhibitor of WRN selectively kills MSI-H cancer cells and phenocopies WRN genetic defects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1628.
Abstract 705: Potentiation of immunotherapy by LSD1 modulation
Authors: Wei B. Emond, Rajiv Sawant, Matthis Geitmann, Johan Winquist, Peter Brandt, Ulf Bremberg, Per Källblad, Vendela Parrow, Claes Andersson, Kristin Blom, Nasrin Najafi, Tobias Bergström, Fredrik J. Swartling, Mats Hellström, Konrad F. Koehler
Journal: Cancer Research (2023)

Abstract LSD1 has emerged as a potential therapeutic target to increase the effectiveness of cancer immunotherapy. We have developed a series of novel small molecules, exemplified by the lead substance BEA-17, that modulates LSD1 via binding to an allosteric site, without directly inhibiting its enzymatic activity. In cells, BEA-17 induces a reduction of LSD1 levels. In addition, BEA-17 upregulates the expression of endogenous retroviral genes and T cell-attractant chemokines and does so in an LSD1-dependent manner. In a co-culture of HeLa and PBMCs, BEA-17 increases cell kill of cancer cells by immune effector T cells, also in an LSD1-dependent manner. In a CT26 syngeneic animal model of colon cancer, BEA-17 potentiates the activity of anti-PD1 inhibitors. Finally, in a syngeneic GL261 animal model of glioblastoma, BEA-17 increases the effectiveness of standard-of-care temozolomide + radiation. Citation Format: Wei B. Emond, Rajiv Sawant, Matthis Geitmann, Johan Winquist, Peter Brandt, Ulf Bremberg, Per Källblad, Vendela Parrow, Claes Andersson, Kristin Blom, Nasrin Najafi, Tobias Bergström, Fredrik J. Swartling, Mats Hellström, Konrad F. Koehler. Potentiation of immunotherapy by LSD1 modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 705.
Abstract 1226: SETD2 loss in renal epithelial cells induces epithelial to mesenchymal transition in a TGFβ-independent manner
Authors: Tianchu Wang, Ryan Wagner, Ryan Hlady, Sungho Kim, Xiaoyu Pan, Thai Ho, Keith Robertson
Journal: Cancer Research (2023)

Abstract Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC) and accounts for majority of the deaths from renal cancer. SETD2, the sole histone methyltransferase that catalyzes trimethylation of lysine 36 on histone H3 (H3K36me3), is frequently mutated in ccRCC. Studies have shown that SETD2 mutations are often subclonal and the mutation rate dramatically increases from 25% in primary ccRCC to more than 60% in metastatic ccRCC, suggesting SETD2 loss plays an important role in renal cancer metastasis. However, mechanisms underpinning how SETD2 mutation drives invasion and metastasis in ccRCC is largely unknown. Here, by performing RNA-seq and ATAC-seq in a non-tumorigenic renal epithelial cell line isogenic for SETD2 loss-of-function, we found that SETD2 inactivation induces dramatic changes in the transcriptome and drastically enhances chromatin accessibility, which allows binding of a variety of transcription factors. We also discovered that SETD2 loss induces a TGFβ-independent EMT program, which is a major pathway linked to metastasis. Correlation of RNA-seq with ATAC-seq identifies SOX2, OCT2 and PRRX1 as key transcription factors promoting the SETD2 loss-driven EMT program. Furthermore, we found that this distinct EMT program is in part triggered by secreted factors, which suggests that SETD2 mutation promotes a metastasis-permissive tumor microenvironment through paracrine signaling. In summary, our findings reveal that SETD2 is a key regulator of EMT phenotypes that may explain the role of SETD2 mutations in ccRCC metastasis and further uncover potential therapeutic targets for SETD2-mutant ccRCC patients. Citation Format: Tianchu Wang, Ryan Wagner, Ryan Hlady, Sungho Kim, Xiaoyu Pan, Thai Ho, Keith Robertson. SETD2 loss in renal epithelial cells induces epithelial to mesenchymal transition in a TGFβ-independent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1226.
Abstract 6225: SERPINB3 promotes the aggressive basal-like/squamous subtype and correlates with poor prognosis in pancreatic ductal adenocarcinoma through metabolic reprogramming
Authors: Yuuki Ohara, Wei Tang, Liu Huaitian, Shouhui Yang, Peijun He, Helen Cawley, Paloma Valenzuela, Lin Zhang, Jochen Gaedcke, B. Michael Ghadimi, Matthias M. Gaida, Frank Bergmann, H. Richard Alexander, Nader Hanna, Stefan Ambs, S. Perwez Hussain
Journal: Cancer Research (2023)

Abstract In this study, we aimed to find genes with a key function in the development of molecular subtypes in pancreatic ductal adenocarcinoma (PDAC). Through transcriptome analysis, we discovered that the endogenous serine/cysteine proteinase inhibitor SERPINB3 (squamous cell carcinoma antigen 1, SCCA1) was distinctively upregulated in the basal-like/squamous subtype, known as an aggressive subtype, and this upregulation associated with decreased patient survival in both a test (N=123) and a validation cohort (N=84). In additional investigations of the tumor metabolome and transcriptome using PDAC patient tumors and cell lines, SERPINB3 and the basal-like/squamous subtype showed a robust relationship with upregulated levels of amino acids (e.g., hydroxyproline) whereas SERPINB3 promoted a gene signature indicative of the basal-like/squamous subtype. Additional mechanistic studies revealed that SERPINB3 and hydroxyproline promoted the migration/invasion of PDAC cells. Moreover, SERPINB3 also promoted metastasis in an orthotopic mouse model of PDAC through stromal factors that increased tumor microvessel density. To conclude, inhibiting SERPINB3 function may attenuate disease progression of the basal-like/squamous subtype in PDAC through changes to the tumor stroma and tumor metabolism. Citation Format: Yuuki Ohara, Wei Tang, Liu Huaitian, Shouhui Yang, Peijun He, Helen Cawley, Paloma Valenzuela, Lin Zhang, Jochen Gaedcke, B. Michael Ghadimi, Matthias M. Gaida, Frank Bergmann, H. Richard Alexander, Nader Hanna, Stefan Ambs, S. Perwez Hussain. SERPINB3 promotes the aggressive basal-like/squamous subtype and correlates with poor prognosis in pancreatic ductal adenocarcinoma through metabolic reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6225.
Abstract 1224: Quaking overexpression downregulates epithelial-mesenchymal transition in lung cancer cells
Authors: Ying-Shiun Kao, Jung-Jyh Hung
Journal: Cancer Research (2023)

Abstract Background: Lung cancer is the leading cause of cancer death worldwide. Tumor recurrence is the most common cause of treatment failure after surgical resection. Quaking (QKI) is a functional protein that mediate alternative splicing, which belongs to the STAR family of the KH domain, containing RNA binding proteins. QKI regulate various genes via alternative splicing and circRNA formation during epithelial-mesenchymal transition (EMT). QKI takes an important part in tumorigenesis. QKI has been reported to be associated with progression of human cancer. However, several studies have indicated that QKI was associated with repression of EMT. Furthermore, the prognostic value of QKI in lung cancer patients and its regulatory mechanisms in EMT in lung cancer cells remains unknown. Materials and Methods: A total of 79 patients with resected lung adenocarcinoma were included in the study. QKI expression was determined by immunohistochemistry in tumor specimens. The prognostic value of QKI overexpression and its relationship with clinicopathological variables were investigated. QKI knockdown was performed in H1299 and A549 cells. Western blotting analysis was performed to demonstrated QKI, E-cadherin and vimentin expression. Results: QKI overexpression was significantly associated with female gender (P = 0.045). There was no significant association between QKI overexpression and predominant pattern group (lepidic/acinar/papillary vs. micropapillary/solid) (P = 0.180). Univariate analysis indicated that predominant pattern group (lepidic/acinar/papillary vs. micropapillary/solid) (P = 0.006) was a significant prognostic factor for worse recurrence-free survival (RFS). QKI overexpression (P = 0.042) was a significant prognostic factor for better RFS. Increased vimentin expression and decreased E-cadherin expression were identified in H1299 and A549 cells after QKI knockdown. Conclusions: QKI overexpression has the potential to be a significant prognostic factor for better RFS in patients with resected lung adenocarcinoma. Increased vimentin expression and decreased E-cadherin expression were identified in H1299-QKIi cells. QKI may possess the ability to inhibit invasion and migration through repressing EMT. Citation Format: Ying-Shiun Kao, Jung-Jyh Hung. Quaking overexpression downregulates epithelial-mesenchymal transition in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1224.
Abstract 1901: Analysis of the survivin expression in breast tumor tissue from black and white cancer patients
Authors: Kerrie Brown, Yisheng V. Fang, Umesh T. Sankpal
Journal: Cancer Research (2023)

Abstract Breast cancer is the most common cancer diagnosed and the leading cause of cancer-related deaths in women. Breast cancer disproportionately affects Black women who have significantly higher mortality rates compared to White women with breast cancer. Although factors like access to healthcare and socioeconomic status contribute significantly to this disparity, there is a need to understand the underlying biological mechanisms that might play an important role. Survivin is a protein that belongs to the inhibitor of apoptosis family. Along with its anti-apoptotic function, it is also involved in the progression of the cell cycle. Survivin is normally expressed during development with no expression detected in most adult differentiated tissues. However, high expression of this protein is found in many cancers which correlates with poor prognosis. The goal of this study was to determine the expression of survivin in tumor tissue from Black and White breast cancer patients. Our first approach was to analyze the TCGA database to confirm our hypothesis that there is differential expression of survivin between the two racial groups and within different subtypes of breast cancer. Secondly, we used immunohistochemical analysis to investigate the expression of survivin in patient tumor tissue samples obtained from Black and White breast cancer patients. Results from the analysis of the TCGA database indicate significantly higher expression of survivin in tumors from Black patients compared to White. High survivin expression is also correlated with higher mortality rates. Immunohistochemical analysis of breast tumors also demonstrated higher expression of survivin in tumor tissue from Black patients. We also observed higher nuclear expression in Black patients compared to White patients. Differential expression was also observed between different subgroups of breast cancer. High expression was seen in the most aggressive triple negative (TNBC) form of breast cancer, which is known to disproportionately occur at higher rates in Black women. Our results along with data available in literature, suggest that survivin plays an important role in breast cancer progression (in correlation to race) and could be a useful diagnostic and/or prognostic marker or a therapeutic target. Citation Format: Kerrie Brown, Yisheng V. Fang, Umesh T. Sankpal. Analysis of the survivin expression in breast tumor tissue from black and white cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1901.
Abstract 116: A novel murine model for interrogating tumor heterogeneity in non-small cell lung cancer
Authors: Michael S. Oh, Jensen W. Abascal, Linh M. Tran, Ramin Salehi-Rad, Raymond J. Lim, Bitta P. Kahangi, William P. Crosson, Edgar Perez Reyes, Jacey Yang, Cara Yeah, Kostyantyn Krysan, Bin Liu, Steven M. Dubinett
Journal: Cancer Research (2023)

Abstract Treatment for non-small cell lung cancer (NSCLC) has been transformed by the use of immune checkpoint inhibitors (ICIs), which promote the ability of the immune system to attack cancer cells. Resistance to these therapies thus represents a major barrier to effectively treating patients with NSCLC. Tumor heterogeneity has been identified as an important factor that may mediate ICI resistance, and prior analyses of NSCLC tumors have accordingly shown that greater tumor heterogeneity is correlated with diminished response to ICIs. However, the exact mechanisms of heterogeneity-mediated resistance remain unclear, and there exist a lack of models for studying the impact of tumor heterogeneity on therapeutic efficacy in NSCLC. To address this issue, we have developed a novel murine model of NSCLC that incorporates a system of clonal cell lines to precisely modulate tumor heterogeneity. Specifically, we isolated single tumor cells from a murine NSCLC cell line harboring 3 common driver mutations (KrasG12DTp53+/−Lkb1−/−, or “KPL”). We additionally isolated single cells after mutagenizing the KPL line with the alkylating agent N-methyl-N-nitrosourea, in order to obtain clones that better reflect the higher tumor mutation burden often seen in NSCLC. Clonal cell lines were derived from these single cells and then analyzed using whole exome sequencing to verify clonality and characterize their mutational profile. Phylogenetic analysis of mutations yielded categorization of these clones into 5 clusters. Clones within the same cluster demonstrated comparable in vivo growth kinetics and similar response to anti-PD-1 immunotherapy. Combinations of these clones can be used to recapitulate various levels of heterogeneity and to form tumors with differing responses to PD-1 inhibition. Our results validate this system of clonal cell lines as a model of NSCLC that can modify multiple aspects of tumor heterogeneity and thus provide insights into the effects of tumor heterogeneity on ICIs and other immunotherapies. Citation Format: Michael S. Oh, Jensen W. Abascal, Linh M. Tran, Ramin Salehi-Rad, Raymond J. Lim, Bitta P. Kahangi, William P. Crosson, Edgar Perez Reyes, Jacey Yang, Cara Yeah, Kostyantyn Krysan, Bin Liu, Steven M. Dubinett. A novel murine model for interrogating tumor heterogeneity in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 116.
Abstract 1296: Targeting nuclear AURKA and hypoxia signaling pathway attenuates metastatic burden in triple negative breast cancer
Authors: Abha Maskey, Kristina Marinak Whately, Elena N. Pugacheva
Journal: Cancer Research (2023)

Abstract Despite remarkable progress in diagnosis and treatment, metastasis from the primary tumor to distant organs is responsible for over 90% of cancer deaths. Therefore, there is a need to understand the drivers of the process to detect, target, and develop therapeutics to treat metastases better and extend their lifespan. Aurora-A Kinase (AURKA) is a serine/threonine kinase that typically localizes in the cytoplasm. However, the nuclear localization of AURKA (N-AURKA) has been reported in multiple cancers and correlates with poor survival and the advanced/metastatic stage of the disease. AURKA is often present in the nucleus of metastatic Triple Negative Breast Cancer (TNBC) cells and patient biopsies compared to non-metastatic cells. Moreover, induced translocation of AURKA to the nucleus in experimental models of TNBC results in a 5-fold increase in metastases to the bones, lungs, and liver compared to AURKA in the cytoplasm. We have previously shown that N-AURKA under normoxic conditions binds to HIF1A/1B and leads to induction of hypoxia signaling via transactivation of Hypoxia Inducible Factors (HIFs)-dependent genes, including migration/invasion, survival/death, and stemness, promoting early cancer dissemination. Transactivation of HIF1-genes requires cofactor p300/CBP. It is currently unknown if N-AURKA/HIF1 transcription is p300 dependent. In this study, we used the small molecular inhibitor Chetomin to disrupt the interaction of HIF1A and co-activator CBP/p300 in experimental TNBC and animal models combined with AURKA inhibitor Alisertib. Disruption of the hypoxia signaling pathway significantly decreases the transactivation of HIF-dependent genes, including migration/invasion, survival/death, and stemness in N-AURKA cells. Moreover, in mouse models, inhibition of HIF1 activity via treatment with Chetomin in combination with AURKA inhibitor Alisertib significantly decreased metastatic burden suggesting that p300 binding to AURKA/HIF complex is critical for gene expression and enabling metastatic dissemination/colonization. Our studies show the mechanistic relationship between N-AURKA and hypoxia signaling and lay the foundation for developing novel combination treatment strategies to improve patient outcomes. Citation Format: Abha Maskey, Kristina Marinak Whately, Elena N. Pugacheva. Targeting nuclear AURKA and hypoxia signaling pathway attenuates metastatic burden in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1296.
Abstract 1687: ATPase copper transporting beta (ATP7B) contributes to acquired docetaxel resistance in human prostate cancer
Authors: Liankun Song, Vyvyan Nguyen, Jun Xie, Matthew Tippin, Le TP Truong, Christopher A. Blair, Beverly Wang, Edward Uchio, Xiaolin Zi
Journal: Cancer Research (2023)

Abstract Docetaxel has been the standard first-line chemotherapy for lethal metastatic prostate cancer (mPCa) since 2004, but the resistance to docetaxel treatment is common. The molecular mechanisms of docetaxel resistance remain largely unknown and could be amenable to interventions that mitigate resistance. We have recently discovered that several docetaxel resistant mPCa cell lines exhibit less uptake of cellular copper and express markedly higher levels of ATP7B protein without significant changes in the protein expression levels of other copper transporters, such as ATPase copper transporting alpha (ATP7A) and high affinity copper uptake protein 1 (CTR1). Knock-down of ATP7B by silencing RNAs sensitized docetaxel resistant-mPCa cells to the growth inhibitory and apoptotic effects of docetaxel. Importantly, deletions of ATP7B in mPCa tissues predict significantly better survival of patients after their first chemotherapy than those with wild-type ATP7B (P = 0.0006). In addition, Disulfiram (DSF), an FDA approved drug for treatment of alcohol dependence, in combination with copper, significantly enhanced the in vivo antitumor effects of docetaxel in a docetaxel resistant xenograft tumor model. Our analyses also revealed that DSF and copper engaged with ATP7B to decrease protein levels of COMM domain-containing protein 1 (COMMD1), S-phase kinase associated protein 2 (Skp2) and clusterin and markedly increase protein expression of cyclin-dependent kinase inhibitor 1 (p21/WAF1). Taken together, our results suggest that ATP7B is a clinically relevant and key target for improving the efficacy of docetaxel for treatment of mPCa. Citation Format: Liankun Song, Vyvyan Nguyen, Jun Xie, Matthew Tippin, Le TP Truong, Christopher A. Blair, Beverly Wang, Edward Uchio, Xiaolin Zi. ATPase copper transporting beta (ATP7B) contributes to acquired docetaxel resistance in human prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1687.